Compositions of GLP-1 peptides and preparation thereof

ABSTRACT

The invention relates to pharmaceutical compositions comprising a first type of granules and a second type of granules, wherein said first type of granules comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and no GLP-1 peptide, and wherein said second type of granules comprises a GLP-1 peptide and no salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, as well as the intermediate granules, processes for the preparation of the granules and compositions, and use thereof in medicine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/157,363, filed Jan. 25, 2021 which is a continuation of a U.S.application Ser. No. 14/386,589, filed Sep. 19, 2014, issued as U.S.Pat. No. 10,933,120, granted on Mar. 2, 2021, which is a 35 U.S.C. § 371National Stage application of International ApplicationPCT/EP2013/055362 (WO 2013/139694), filed Mar. 15, 2013, which claimspriority to European Patent Application 12160743.6, filed Mar. 22, 2012,and to European Patent Application 13153459.6, filed Jan. 31, 2013; thisapplication claims priority under 35 U.S.C. § 119 to U.S. ProvisionalApplication 61/748,840, filed Jan. 4, 2013; the contents of which areincorporated by reference in their entirety.

The present invention is directed to compositions comprisingpharmacologically active agents, such as GLP-1, and a delivery agent aswell as processes for their preparation and use thereof in medicine.

INCORPORATION-BY-REFERENCE OF THE SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Mar. 25, 2022, isnamed 8481US05_SeqList_ST25.txt and is 2 kilobytes in size.

BACKGROUND

One of the main challenges in oral delivery of proteins and peptides isthe inability of these compounds to be readily transported across themembranes of the gastrointestinal tract. The delivery agent SNAC haspreviously been shown to improve the bioavailability of orallyadministered peptides. The present invention relates to furtherimprovements of the bioavailability by oral administration ofcompositions of such peptides, in particular of GLP-1 peptides.

SUMMARY

In one embodiment the invention relates to a pharmaceutical compositioncomprising a first type and a second type of granules, wherein saidfirst type of granules comprises a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and no GLP-1 peptide, andwherein said second type of granules comprises a GLP-1 peptide and nosalt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodimentsthe term “granule” refers to small particles gathered into a large mass.

In one embodiment the invention relates to a process of producing apharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, whereinthe process comprises the steps: a) mixing a GLP-1 peptide with a fillerand/or a binder; b) dry granulation of the mixture of step a; c) mixingthe granules obtained in step b with a composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino) caprylic acid; and d) optionally addingfurther lubricant, wherein the mixture of step a does not comprise asalt of N-(8-(2-hydroxybenzoyl)amino) caprylic acid.

In one embodiment the invention relates to a process of producing apharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, whereinthe process comprises the steps: a) mixing a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or afiller; b) dry granulation of the mixture of step a; c) mixing thegranules obtained in step b with a composition comprising a GLP-1peptide; and d) optionally adding further lubricant, wherein the mixtureof step a does not comprise a GLP-1 peptide.

In one embodiment the invention relates to a process of producing apharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, whereinthe process comprises the steps: a) mixing a GLP-1 peptide with a fillerand/or a binder; b) dry granulation of the mixture of step a; c) mixinga salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, optionally alubricant and/or a filler; d) dry granulation of the mixture of step c;e) mixing the granules obtained in step b with the granules obtained instep d; and f) optionally adding further lubricant, wherein the mixtureof step a does not comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and wherein the mixture of step c does not comprise aGLP-1 peptide.

In one embodiment the invention relates to a granule comprising a saltof N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a lubricant, optionally afiller, and no GLP-1 peptide. In one embodiment the invention relates toa process of producing a granule comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid, wherein the processcomprises the steps: a) mixing a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid (such as SNAC) with alubricant and/or a filler; and b) dry granulation of the mixture of stepa, wherein the mixture of step a does not comprise a GLP-1 peptide.

In one embodiment the invention relates to a granule comprising a GLP-1peptide, a filler, a binder, and no salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid. In one embodiment theinvention relates to a process of producing a granule comprising a GLP-1peptide, wherein the process comprises the steps: a) mixing a GLP-1peptide, optionally a filler and/or a binder; and b) roller compactingthe mixture of step a, wherein the mixture of step a does not comprise asalt of N-(8-(2-hydroxybenzoyl)amino) caprylic acid.

In one embodiment the invention relates to a pharmaceutical compositionor a granule obtained by the process as defined herein.

In one embodiment the invention relates to a composition or a granule asdefined herein for use in medicine, such as for treatment of diabetes orobesity, wherein said composition is administered orally. In oneembodiment the invention relates to a method for treatment of diabetesor obesity comprising administering the composition as defined herein toa patient in need thereof, wherein said composition is administeredorally.

DESCRIPTION

The present inventors surprisingly found that the dissolution propertiesof tablets manufactured from the same composition (i.e. same type andthe same amounts of excipients and delivery agent) was determined by thedesign of the granules from which the tablets were formed.

Furthermore, the present inventors found that the dissolution behavioursurprisingly had a marked effect on the bioavailability of GLP-1 peptidefrom the composition, such as the tablet. Thus, the present inventorshave shown that the bioavailability of solid tablets manufactured fromvarious granule designs can be predicted from in vitro data, i.e.dissolution data. In one embodiment this invention providescompositions, granules and methods for their preparation with improvedbioavailability of the GLP-1 peptide.

Generally, the term “bioavailability” as used herein refers to thefraction of an administered dose of an active pharmaceutical ingredient(API) and/or active moieties, such as a GLP-1 peptide as defined herein,which reaches the systemic circulation un-changed or in another activeform. By definition, when an API and/or active moieties are administeredintravenously, its bioavailability is 100%. However, when it isadministered via other routes (such as orally), its bioavailabilitydecreases (due to incomplete absorption and/or first-pass metabolism).Knowledge about bioavailability is important when calculating dosagesfor non-intravenous routes of administration.

Absolute oral bioavailability is calculated as the relative exposure ofthe API and/or active moieties in systemic circulation following oraladministration (estimated as the area under the plasma concentrationversus time curve) compared to the exposure of the API followingintravenous administration.

Pharmaceutical Compositions

In some embodiments the invention relates to a pharmaceuticalcomposition comprising a first type and a second type of granules,wherein said first type of granules comprises a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and said second type ofgranules comprises a GLP-1 peptide. In some embodiments the first typeof granules further comprises a lubricant, such as magnesium stearate.In some embodiments the first type of granules further comprises afiller, such as microcrystalline cellulose. Accordingly, the first typeof granules may further comprise a lubricant and optionally a filler. Insome embodiments the second type of granules further comprises a filler,such as microcrystalline cellulose. In some embodiments the second typeof granules further comprises a binder, such as povidone. Accordingly,the second type of granules may further comprise a filler and optionallya binder. In some embodiments the composition further comprises anextragranular lubricant, such as magnesium stearate.

In some embodiments N-(8-(2-hydroxybenzoyl)amino)caprylic acid isreferred to as “NAC”.

In some embodiments the first type of granules comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid does not contain a GLP-1peptide. In some embodiments the second type of granules comprising aGLP-1 peptide does not contain a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments thepharmaceutical composition comprises a first type and a second type ofgranules, wherein said first type of granules comprises a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and no GLP-1 peptide, andwherein said second type of granules comprises a GLP-1 peptide and nosalt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

In some embodiments the term “granule” refers to particles gathered intolarger particles.

In some embodiments the invention relates to a pharmaceuticalcomposition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylicacid and a GLP-1 peptide, wherein the release of said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is simultaneous with orfaster than the release of said GLP-1 peptide as determined bydissolution testing using Assay (I). In some embodiments the inventionrelates to a pharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, whereinthe release of said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidis simultaneous with or faster than the release of said GLP-1 peptide.

In some embodiments the term “release” when used with reference toN-(8-(2-hydroxybenzoyl)amino)caprylic acid and optionally compared torelease of GLP-1 peptide is determined within 30 minutes, such as within25, 20, 15 minutes, or such as within 10 or 5 minutes, as determined bydissolution testing using Assay (I). Accordingly, the release may bedetermined within 30 minutes of dissolution testing using Assay (I). Insome embodiments the release of said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid when referred to as “fasterthan” the release of said GLP-1 peptide is determined within 30 minutes,such as within 25, 20, 15 minutes, or such as within 10 or 5 minutes, asdetermined by dissolution testing using Assay (I). In some embodimentsthe release of said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidwhen referred to as “faster than” the release of said GLP-1 peptide isdetermined within 30 minutes, such as within 25, 20, 15 minutes, or suchas within 10 or 5 minutes, as determined by dissolution testing usingAssay (I) at pH 2.5.

In some embodiments the release of said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid when referred to as“simultaneous with” the release of said GLP-1 peptide is determinedwithin 30 minutes, such as within 25, 20, 15 minutes, or such as within10 or 5 minutes, as determined by dissolution testing using Assay (I).In some embodiments the release of said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid when referred to as“simultaneous with” the release of said GLP-1 peptide is determinedwithin 30 minutes, such as within 25, 20, 15 minutes, or such as within10 or 5 minutes, as determined by dissolution testing using Assay (I) atpH 2.5.

In some embodiments the invention relates to a pharmaceuticalcomposition according to any one of the preceding claims, wherein theamount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidpeaks within the first 60 minutes as determined by dissolution testingusing Assay (I) at pH 2.5. In some embodiments the invention relates toa pharmaceutical composition, wherein the amount of dissolved salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid peaks within the first 30minutes as determined by dissolution testing using Assay (I) at pH 2.5.In some embodiments the amount of dissolved salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid peaks within 55 minutes, suchas within 50, 45 or 40 minutes, as determined by dissolution testingusing Assay (I) at pH 2.5. In some embodiments the amount of dissolvedsalt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid peaks within 39 or 38minutes, such as within 37, 36, or 35 minutes, as determined bydissolution testing using Assay (I) at pH 2.5. In some embodiments theamount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidpeaks within 34 minutes, such as within 33, 32, or 31 minutes, asdetermined by dissolution testing using Assay (I) at pH 2.5. In someembodiments the amount of dissolved salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid peaks within 31 minutes, suchas within 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, or 60 minutesas determined by dissolution testing using Assay (I) at pH 2.5.

In some embodiments the composition comprises granules which have beenmanufactured by dry granulation. In some embodiments the compositioncomprises granules which have been manufactured by roller compaction. Insome embodiments the moldings from the roller compactions process arecomminuted into granules. As used herein the term “composition” refersto a pharmaceutical composition.

In some embodiments the composition is in the form of a solid dosageform. In some embodiments the composition is in the form of a tablet. Insome embodiments the composition is in the form of a capsule. In someembodiments the composition is in the form of a sachet.

In some embodiments the composition or granule comprises at least onepharmaceutically acceptable excipient. The term “excipient” as usedherein broadly refers to any component other than the active therapeuticingredient(s). The excipient may be an inert substance, which is inertin the sense that it substantially does not have any therapeutic and/orprophylactic effect per se. The excipient may serve various purposes,e.g. as a delivery agent, absorption enhancer, vehicle, filler (alsoknown as diluents), binder, lubricant, glidant, disintegrant,crystallization retarders, acidifying agent, alkalizing agent,preservative, antioxidant, buffering agent, chelating agent, complexingagents, surfactant agent, emulsifying and/or solubilizing agents,sweetening agents, wetting agents stabilizing agent, colouring agent,flavouring agent, and/or to improve administration, and/or absorption ofthe active substance. A person skilled in the art may select one or moreof the aforementioned excipients with respect to the particular desiredproperties of the solid oral dosage form by routine experimentation andwithout any undue burden. The amount of each excipient used may varywithin ranges conventional in the art. Techniques and excipients whichmay be used to formulate oral dosage forms are described in Handbook ofPharmaceutical Excipients, 6th edition, Rowe et al., Eds., AmericanPharmaceuticals Association and the Pharmaceutical Press, publicationsdepartment of the Royal Pharmaceutical Society of Great Britain (2009);and Remington: the Science and Practice of Pharmacy, 21th edition,Gennaro, Ed., Lippincott Williams & Wilkins (2005).

In some embodiments the composition or granule comprises a filler, suchas lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®,various grades of Pharmatose®, Microtose® or Fast-FloC®),microcrystalline cellulose (various grades of Avicel®, Elcema®,Vivacel®, Ming Tai® or Solka-Floc®), other cellulose derivatives,sucrose, sorbitol, mannitol, dextrins, dextrans, maltodextrins,dextrose, fructose, kaolin, mannitol, sorbitol, sucrose, sugar, starchesor modified starches (including potato starch, maize starch and ricestarch), calcium phosphate (e.g. basic calcium phosphate, calciumhydrogen phosphate, dicalcium phosphate hydrate), calcium sulphate,calcium carbonate, or sodium alginate. In some embodiments the filler ismicrocrystalline cellulose, such as Avicel PH 101.

In some embodiments the composition or granule comprises a binder, suchas lactose (e.g. spray-dried lactose, α-lactose, β-lactose, Tabletose®,various grades of Pharmatose®, Microtose® or Fast-FloC®),microcrystalline cellulose (various grades of Avicel®, Elcema®,Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose,L-hydroxypropylcellulose (low-substituted), hypromellose (HPMC) (e.g.Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd, such as, e.g., the4,000 cps grades of Methocel E and Metolose 60 SH, the 4,000 cps gradesof Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cpsgrades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 gradesof Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A,Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose,ethylcellulose, sodium carboxymethylcellulose, other cellulosederivatives, sucrose, dextrins, maltodextrins, starches or modifiedstarches (including potato starch, maize starch and rice starch),calcium lactate, calcium carbonate, acacia, sodium alginate, agar,carrageenan, gelatin, guar gum, pectin, PEG, or povidone. In someembodiments the binder is povidone, such as povidone K 90.

In some embodiments the composition or granule comprises a disintegrant,such as alginic acid, alginates, microcrystalline cellulose,hydroxypropyl cellulose, other cellulose derivatives, croscarmellosesodium, crospovidone, polacrillin potassium, sodium starch glycolate,starch, pregelatinized starch, or carboxymethyl starch (e.g. Primogel®and Explotab®).

In some embodiments the composition or granule comprises a lubricant,such as stearic acid, magnesium stearate, calcium stearate or othermetallic stearate, talc, waxes, glycerides, light mineral oil, glycerylbehenate, hydrogenated vegetable oils, sodium stearyl fumarate,polyethylene glycols, alkyl sulfates, or sodium benzoate. In someembodiments the composition or granule comprises a lubricant, such asmagnesium silicate, talc, or colloidal silica. In some embodiments thelubricant is magnesium stearate.

In some embodiments the composition or granule comprises one or moreexcipients selected from crystallization retarders, such as Povidone,etc.; solubilizing agents (also known as surfactants), such as anionicsurfactants (e.g. Pluronic or Povidone), cationic surfactants, nonionicsurfactants, and/or zwitterionic surfactants; colouring agents,including dyes and pigments, such as Iron Oxide Red or Yellow, titaniumdioxide, and/or talc; and/or pH control agents, such as citric acid,tartaric acid, fumaric acid, sodium citrate, dibasic calcium phosphate,and/or dibasic sodium phosphate.

In some embodiments the composition comprises at least 60% (w/w)delivery agent, less than 10% (w/w) binder, 5-40% (w/w) filler, and lessthan 10% (w/w) lubricant.

In some embodiments the composition comprises at least 60% (w/w), suchas 65-75% (w/w), 60-80% (w/w), or 50-90% (w/w), delivery agent. In someembodiments the composition comprises at least 70% (w/w), such as 70-80%(w/w), delivery agent.

In some embodiments the composition comprises 0.1-10% (w/w), such as0.2-4% (w/w) or 0.5-3% (w/w), binder. In some embodiments thecomposition comprises 1.5-2.5% (w/w), such as 1.7-2.3% (w/w), 1.8-2.2%(w/w), or 1.9-2.1% (w/w), binder. In some embodiments the compositioncomprises 1% (w/w) or 2% (w/w) binder.

In some embodiments the composition comprises 5-40% (w/w), such as10-30% (w/w) or 5-25% (w/w), filler. In some embodiments the compositioncomprises 10-25% (w/w), such as 17-23% (w/w), 18-22% (w/w), or 19-21%(w/w), filler. In some embodiments the composition comprises 10.9% (w/w)or 18% (w/w) filler, or comprises 19.5% (w/w) or 20.5 (w/w) filler.

In some embodiments the composition comprises 0.1-10% (w/w) or 0.5-5%(w/w), such as 1-3.5% (w/w) or 1% (w/w), lubricant. In some embodimentsthe composition comprises 1.5-3% (w/w), such as 2.1-2.7% (w/w), 2.2-2.6%(w/w) or 2.3-2.5% (w/w), lubricant.

Still further, the composition or granule of the invention may beformulated as is known in the art of oral formulations of insulinotropiccompounds.

The composition or granule may be administered in several dosage forms,for example as a tablet; a capsule such as hard capsules, sachet or apowder. The composition or granule may further be compounded in a drugcarrier or drug delivery system, e.g. in order to improve stabilityand/or solubility or further improve bioavailability.

In some embodiments the weight of the tablet is in the range of 150 mgto 1000 mg, such as in the range of 300-600 mg or 350-450 mg.

In some embodiments the invention relates to a first granule comprisingat least 75% (w/w) delivery agent, less than 10% (w/w) lubricant, andoptionally less than 20% filler and no GLP-1 peptide. In someembodiments the invention relates to a first granule comprising at least80% (w/w) delivery agent, less than 10% (w/w) lubricant, and optionallyless than 20% filler and no GLP-1 peptide. In some embodiments the firstgranule comprises 75-90% (w/w), such as 78-88% (w/w), 80-86% (w/w) or82-84% (w/w), delivery agent. In some embodiments the first granulecomprises less than 10% (w/w), such as 1-3% (w/w), 1.5-2.5% (w/w) or1.9-2.3% (w/w), lubricant, In some embodiments the first granulecomprises less than 20%, such as 10-20% (w/w), 12-18% (w/w) or 14-17%(w/w), filler. In some embodiments the first granule comprises no GLP-1peptide. In some embodiments the granule comprises at least 80% (w/w)delivery agent, less than 10% (w/w) lubricant, and optionally less than20% filler.

In some embodiments the invention relates to a second granule comprisinga GLP-1 peptide, at least 15% (w/w) filler and less than 40% (w/w)binder and no salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. Insome embodiments the second granule comprises at least 1%, such as 1-70%(w/w), 2-40% (w/w) or 4-30% (w/w), GLP-1 peptide. In some embodimentsthe second granule comprises at least 20%, such as 40-80% (w/w) or50-75% (w/w), filler. In some embodiments the second granule comprisesless than 30%, such as 5-30% (w/w), 10-28% (w/w) or 15-25% (w/w),binder. In some embodiments the second granule comprises no salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments thegranule comprises a GLP-1 peptide, at least 15% (w/w) filler and lessthan 40% (w/w) binder. In some embodiments the granule comprises a GLP-1peptide, at least 50% (w/w) filler and less than 40% (w/w) binder.

In some embodiments the invention relates to a composition comprising afirst and a second type of granules, wherein the first type of granulecomprises at least 75% (w/w) delivery agent, less than 10% (w/w)lubricant, optionally less than 20% filler and no GLP-1 peptide, andwherein the second type of granule comprises a GLP-1 peptide, at least15% (w/w) filler, less than 40% (w/w) binder and no salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments theinvention relates to a composition comprising a first and a second typeof granules, wherein the first type of granule comprises at least 75%(w/w) delivery agent, less than 10% (w/w) lubricant, less than 20%filler and no GLP-1 peptide, and wherein the second type of granulecomprises a GLP-1 peptide, at least 15% (w/w) filler, less than 40%(w/w) binder and no salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.In some embodiments the invention relates to a composition comprising afirst and a second type of granules, wherein the first type of granulecomprises at least 75% (w/w) delivery agent, less than 10% (w/w)lubricant, and no GLP-1 peptide, and wherein the second type of granulecomprises a GLP-1 peptide, at least 15% (w/w) filler, less than 40%(w/w) binder and no salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

Methods of Preparation of Pharmaceutical Compositions

The composition of the invention may be prepared as is known in the art.In some embodiments the composition or the granule may be prepared asdescribed in the examples herein. In some embodiments the compositionmay be granulated prior to being compressed into tablets. In someembodiments the granules of the invention are manufactured by drygranulation, such as by roller compaction compaction. In someembodiments the moldings from the roller compactions process arecomminuted into granules. The composition may comprise one or moreintragranular parts and an extragranular part, wherein the intragranularparts have been granulated, and wherein the extragranular part has beenadded after granulation. A first intragranular part may comprise theGLP-1 peptide and one or more excipients, and a second intragranularpart may comprise the delivery agent and optionally one or moreexcipients. A first intragranular part may comprise the GLP-1 peptide,filler and/or a binder and a second intragranular part may comprise thedelivery agent, lubricant and filler. The first intragranular part maycomprise the GLP-1 peptide, filler and/or binder and a secondintragranular part may comprise the delivery agent, lubricant and/orfiller. In some embodiments the first intragranular part comprises theGLP-1 agonist (i.e. the GLP-1 peptide), microcrystalline celluloseand/or povidone and the second intragranular part comprises the deliveryagent, magnesium stearate and microcrystalline cellulose. In someembodiments the first intragranular part comprises the GLP-1 agonist(i.e. the GLP-1 peptide), microcrystalline cellulose and/or povidone andthe second intragranular part comprises the delivery agent, magnesiumstearate and/or microcrystalline cellulose. The extragranular part maycomprise a lubricant. In some embodiments the extragranular partcomprises magnesium stearate. In some embodiments the term “fillerand/or binder” or “filler and/or a binder” refers to a filler andoptionally a binder. In some embodiments the term “lubricant and filler”or “lubricant and/or filler” refers to a lubricant and optionally afiller.

To prepare a dry blend of tabletting material, the various componentsare weighed, optionally delumped and then combined. The mixing of thecomponents may be carried out until a homogeneous blend is obtained.

If granules are to be used in the tabletting material, granules may beproduced in a manner known to a person skilled in the art, for exampleby dry granulation techniques in which the pharmaceutically active agentand/or delivery agents are compacted with the excipients to formrelatively large moldings, for example slugs or ribbons, which arecomminuted by grinding, and the ground material serves as the tablettingmaterial to be later compressed into tablets. Suitable equipment for drygranulation includes but is not limited to roller compaction equipmentfrom Gerteis, such as Gerteis MINI-PACTOR.

To compress the tabletting material into a solid oral dosage form, forexample a tablet, a tablet press may be used. In a tabletting press, thetabletting material is filled (e.g. force fed or gravity fed) into a diecavity. The tabletting material is then compressed by a punch withpressure. Subsequently, the resulting compact, or tablet is ejected fromthe tabletting press. The above mentioned compression process issubsequently referred to herein as the “compression process”. Suitabletablet presses include, but are not limited to, rotary tablet pressesand eccentric tablet presses. Examples of tablet presses include, butare not limited to, the Fette 102i (Fette GmbH), the Korsch XL100, theKorsch PH 106 rotary tablet press (Korsch AG, Germany), the Korsch EK-Oeccentric tabletting press (Korsch AG, Germany) and the Manesty F-Press(Manesty Machines Ltd., United Kingdom).

In some embodiments the method of preparation of the tablet comprises i)dry granulation of a mixture comprising the GLP-1 agonist (i.e. theGLP-1 peptide), filler and a binder; ii) dry granulation of a mixturecomprising the delivery agent, lubricant and filler; iii) mixing of thegranules with a lubricant; and then iv) compression of the blend intotablets. In some embodiments the method of preparation of the tabletcomprises i) dry granulation of a mixture comprising the GLP-1 agonist(i.e. the GLP-1 peptide), filler and a binder; ii) dry granulation of amixture comprising the delivery agent, lubricant and/or filler; iii)mixing of the granules with a lubricant; and then iv) compression of theblend into tablets.

In some embodiments the invention relates to a process of producing apharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, whereinthe process comprises the steps: a) mixing a GLP-1 peptide with a fillerand/or a binder; b) dry granulation of the mixture of step a; c) mixingthe granules obtained in step b with a composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino) caprylic acid; and d) optionally addingfurther lubricant. In some embodiments the invention relates to aprocess of producing a pharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, whereinthe process comprises the steps: a) mixing a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or afiller; b) dry granulation of the mixture of step a; c) mixing thegranules obtained in step b with a composition comprising a GLP-1peptide; and d) optionally adding further lubricant. In some embodimentsthe invention relates to a process of producing a pharmaceuticalcomposition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylicacid and a GLP-1 peptide, wherein the process comprises the steps: a)mixing a GLP-1 peptide with a filler and/or a binder; b) dry granulationof the mixture of step a; c) mixing a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid, optionally a lubricantand/or a filler; d) dry granulation of the mixture of step c; e) mixingthe granules obtained in step b with the granules obtained in step d;and f) optionally adding further lubricant.

In one embodiment the invention relates to a process of producing apharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, whereinthe process comprises the steps: a) mixing a GLP-1 peptide with a fillerand/or a binder; b) dry granulation of the mixture of step a; c) mixinga salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, optionally alubricant and/or a filler; d) dry granulation of the mixture of step c;e) mixing the granules obtained in step b with the granules obtained instep d; and f) optionally adding further lubricant, wherein the mixtureof step a does not comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and wherein the mixture of step c does not comprise aGLP-1 peptide.

In one embodiment the invention relates to a granule comprising a saltof N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a lubricant, optionally afiller, and no GLP-1 peptide. In one embodiment the invention relates toa process of producing a granule comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid, wherein the processcomprises the steps: a) mixing a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid (such as SNAC) with alubricant and/or a filler; and b) dry granulation of the mixture of stepa, wherein the mixture of step a does not comprise a GLP-1 peptide.

In one embodiment the invention relates to a granule comprising a GLP-1peptide, a filler, a binder, and no salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid. In one embodiment theinvention relates to a process of producing a granule comprising a GLP-1peptide, wherein the process comprises the steps: a) mixing a GLP-1peptide, optionally a filler and/or a binder; and b) roller compactingthe mixture of step a, wherein the mixture of step a does not comprise asalt of N-(8-(2-hydroxybenzoyl)amino) caprylic acid.

In some embodiments the mixing step comprising mixing of a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or afiller prior to dry granulation has a duration of at least 20 minutes.In some embodiments the mixing step comprising mixing of a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or afiller prior to dry granulation has a duration of at least 30 minutes orat least 40 minutes, such as 50 minutes. In some embodiments the mixingstep comprising mixing of the first type of granules comprising a GLP-1peptide with the second type of granules comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid has a duration of at least 15minutes or at least 20 minutes, such as at least 25 minutes or at least30 minutes.

In some embodiments the invention relates to a pharmaceuticalcomposition obtained by the process as defined herein.

In some embodiments the invention relates to a granule comprising a saltof N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant. In someembodiments the granule comprises a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid, a lubricant, and a filler.In some embodiments the invention relates to a granule comprising aGLP-1 peptide, a filler and a binder. In some embodiments the granule isprepared according to the process as defined herein.

In some embodiments the invention relates to a process of producing agranule comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid,wherein the process comprises the steps: a) mixing a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid (such as SNAC) with alubricant and/or a filler; and b) dry granulation of the mixture of stepa. In some embodiments the mixing step comprising mixing of a salt ofN-(8-(2-hydroxybenzoyl)amino) caprylic acid with a lubricant and/or afiller prior to dry granulation has a duration of at least 20 minutes.In some embodiments the mixing step comprising mixing of a salt ofN-(8-(2-hydroxybenzoyl)amino) caprylic acid with a lubricant and/or afiller prior to dry granulation has a duration of at least 30 minutes orat least 40 minutes, such as 50 minutes.

In some embodiments the invention relates to a process of producing agranule comprising a GLP-1 peptide, wherein the process comprises thesteps: a) mixing a GLP-1 peptide, optionally a filler and/or a binder;and b) roller compacting the mixture of step a.

In some embodiments the invention relates to a granule obtained by theprocess as defined herein.

In some embodiments the lubricant is magnesium stearate. In someembodiments the filler is microcrystalline cellulose. In someembodiments the binder is povidone.

In some embodiments the term “resistance to crushing of tablets” has themeaning defined in section 2.9.8 in the European Pharmacopoeia 7.5, 7thedition 2012; resistance to crushing may be measured inter alia inNewton (N) or kilopond (kP) using a jaw speed of 20 N/s (1 kP equals9.807 N).

In some embodiments the term “roller compaction force” means the forcebetween the rolls of the roller compactor when compacting materials intoa continuous strip of compressed material as determined by a pressuretransducer that converts the hydraulic pressure into electrical signal;the roller compaction force may be measured in kiloNewton (kN) or inkiloNewton per roll width (kN/cm).

In Vitro Methods

Dissolution of compositions of the invention may be determined asdescribed in Assay (I) herein. In some embodiments the dissolutiontesting using Assay (I) is carried out at any one of pH 1.0-8.0. In someembodiments the dissolution testing using Assay (I) is carried out at pH1.0. In some embodiments the dissolution testing using Assay (I) iscarried out at pH 2.5. In some embodiments the dissolution testing usingAssay (I) is carried out at pH 6.8.

GLP-1 Peptides

In one embodiment the composition of the invention comprises a GLP-1peptide. The term “GLP-1 peptide” as used herein refers to a compound,which fully or partially activates the human GLP-1 receptor. In someembodiments the “GLP-1 peptide” binds to a GLP-1 receptor, e.g., with anaffinity constant (K_(D)) or activate the receptor with a potency (EC₅₀)of below 1 μM, e.g. below 100 nM as measured by methods known in the art(see e.g. WO 98/08871) and exhibits insulinotropic activity, whereinsulinotropic activity may be measured in vivo or in vitro assays knownto those of ordinary skill in the art. For example, the GLP-1 peptidemay be administered to an animal with increased blood glucose (e.g.obtained using an Intravenous Glucose Tolerance Test (IVGTT), a personskilled in the art will be able to determine a suitable glucose dosageand a suitable blood sampling regime, e.g. depending on the species ofthe animal, for the IVGTT) and the plasma insulin concentration measuredover time. In some embodiments the GLP-1 peptide is referred to as aGLP-1 agonist.

In some embodiments the GLP-1 peptide is a GLP-1 analogue, optionallycomprising one substituent. The term “analogue” as used herein referringto a GLP-1 peptide (hereafter “peptide”) means a peptide wherein atleast one amino acid residue of the peptide has been substituted withanother amino acid residue and/or wherein at least one amino acidresidue has been deleted from the peptide and/or wherein at least oneamino acid residue has been added to the peptide and/or wherein at leastone amino acid residue of the peptide has been modified. Such additionor deletion of amino acid residues may take place at the N-terminal ofthe peptide and/or at the C-terminal of the peptide. In some embodimentsa simple nomenclature is used to describe the GLP-1 peptide, e.g.,[Aib8] GLP-1(7-37) designates an analogue of GLP-1(7-37) wherein thenaturally occurring Ala in position 8 has been substituted with Aib. Insome embodiments the GLP-1 peptide comprises a maximum of twelve, suchas a maximum of 10, 8 or 6, amino acids which have been alterered, e.g.,by substitution, deletion, insertion and/or modification, compared toe.g. GLP-1(7-37). In some embodiments the analogue comprises up to 10substitutions, deletions, additions and/or insertions, such as up to 9substitutions, deletions, additions and/or insertions, up to 8substitutions, deletions, additions and/or insertions, up to 7substitutions, deletions, additions and/or insertions, up to 6substitutions, deletions, additions and/or insertions, up to 5substitutions, deletions, additions and/or insertions, up to 4substitutions, deletions, additions and/or insertions or up to 3substitutions, deletions, additions and/or insertions, compared to e.g.GLP-1(7-37). Unless otherwise stated the GLP-1 comprises only L-aminoacids.

In some embodiments the term “GLP-1 analogue” or “analogue of GLP-1” asused herein refers to a peptide, or a compound, which is a variant ofthe human Glucagon-Like Peptide-1 (GLP-1(7-37)). GLP-1(7-37) has thesequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 1). In someembodiments the term “variant” refers to a compound which comprises oneor more amino acid substitutions, deletions, additions and/orinsertions.

In one embodiment the GLP-1 peptide exhibits at least 60%, 65%, 70%, 80%or 90% sequence identity to GLP-1(7-37) over the entire length ofGLP-1(7-37). As an example of a method for determination of sequenceidentity between two analogues the two peptides [Aib8]GLP-1(7-37) andGLP-1(7-37) are aligned. The sequence identity of [Aib8]GLP-1(7-37)relative to GLP-1(7-37) is given by the number of aligned identicalresidues minus the number of different residues divided by the totalnumber of residues in GLP-1(7-37). Accordingly, in said example thesequence identity is (31-1)/31.

In one embodiment the C-terminal of the GLP-1 peptide is an amide.

In some embodiments the GLP-1 peptide is GLP-1(7-37) orGLP-1(7-36)amide. In some embodiments the GLP-1 peptide is exendin-4,the sequence of which is HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQID No: 2).

In some embodiments the GLP-1 peptide comprises one substituent which iscovalently attached to the peptide. In some embodiments the substituentcomprises a fatty acid or a fatty diacid. In some embodiments thesubstituent comprises a C16, C18 or C20 fatty acid. In some embodimentsthe substituent comprises a C16, C18 or C20 fatty diacid. In someembodiments the substituent comprises formula (X)

wherein n is at least 13, such as n is 13, 14, 15, 16, 17, 18 or 19. Insome embodiments the substituent comprises formula (X), wherein n is inthe range of 13 to 19, such as in the range of 13 to 17. In someembodiments the substituent comprises formula (X), wherein n is 13, 15or 17. In some embodiments the substituent comprises formula (X),wherein n is 13. In some embodiments the substituent comprises formula(X), wherein n is 15. In some embodiments the substituent comprisesformula (X), wherein n is 17. In some embodiments the substituentcomprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG), such as twoOEG.

In some embodiments the substituent is[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino] ethoxy}ethoxy)acetyl].

In some embodiments the substituent is[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

In some embodiments the GLP-1 peptide is semaglutide, also known asN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37),which may be prepared as described in WO2006/097537, Example 4.

In some embodiments the composition comprises the GLP-1 peptide or apharmaceutically acceptable salt, amide, or ester thereof. In someembodiments the composition comprises the GLP-1 peptide one or morepharmaceutically acceptable counter ions.

In some embodiments the dosage of GLP-1 peptide is in the range of 0.01mg to 100 mg. In some embodiments the composition or granule comprisesan amount of a GLP-1 peptide in the range of at least 1 mg, such as atleast 5 mg or at least 10 mg. In some embodiments the composition orgranule comprises 10 mg GLP-1 peptide.

In some embodiments the composition comprises an amount of a GLP-1peptide in the range of 0.05 to 25 μmol, such as in the range of 0.5 to20 μmol.

In some embodiments the GLP-1 peptide is selected from one or more ofthe GLP-1 peptides mentioned in WO93/19175, WO96/29342, WO98/08871,WO99/43707, WO99/43706, WO99/43341, WO99/43708, WO2005/027978,WO2005/058954, WO2005/058958, WO2006/005667, WO2006/037810,WO2006/037811, WO2006/097537, WO2006/097538, WO2008/023050,WO2009/030738, WO2009/030771 and WO2009/030774.

In some embodiments the GLP-1 peptide is selected from the groupconsisting ofN-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide;N-epsilon26{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy}acetyl[desaminoHis7, Arg34] GLP-1-(7-37);N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy] ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][,DesaminoHis7, Glu22 Arg26, Arg 34,Phe(m-CF3)28]GLP-1-(7-37)amide;N-epsilon26-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{4-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]butyryl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(trans-19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl[Aib8, Lys 26]GLP-1(7-37)amide; N-epsilon26[2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-carboxynonadecanoylamino] methyl)cyclohexylcarbonylamino]-4-carboxybutanoylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8, Lys26] GLP-1 (7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]-butyrylamino}butyrylamino)butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]-dodecanoylamino}butyrylamino)butyrylamino] ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide;N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyryl-amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1-(7-34);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36)amide;N-epsilon26-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Lys26,Arg34]GLP-1-(7-36)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide;N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino} propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxy} acetyl [Aib8,Glu22,Arg26,Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyhepta-decanoyl)piperidin-4-ylcarbonylamino]3-carboxy-propionylamino)ethoxy)ethoxy] acetylamino) ethoxy] ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26, Arg34,Phe(m-CF3)28] GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl} amino)butyrylamino]ethoxy} ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy} ethoxy)acetyl] [DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino] ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Glu30,Arg34, Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino} butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-(3-((2-(2-(2-(2-(2-Hexadecyloxyethoxy)ethoxy)ethoxy) ethoxy)ethoxy))propionyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide;N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy] acetyl)ethoxy)ethoxy)acetyl)}-[desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37] GLP-1-(7-37)amide;N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxy-butyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy) acetyl)}-[desaminoHis7,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37)amide;N-epsilon37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(octadecanoyl-amino)ethoxy)ethoxy)acetylamino)ethoxy) ethoxy)acetylamino) ethoxy)ethoxy)acetyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1 (7-37)amide;N-epsilon37-[4-(16-(1H-Tetrazol-5-yl)hexadecanoylsulfamoyl) butyryl][DesaminoHis7,Glu22,Arg26, Arg34, Lys37]GLP-1-(7-37)amide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyrylamino] ethoxy}ethoxy) acetylamino]ethoxy} ethoxy)acetyl][DesaminoHis7,Glu22,Arg26, Arg34,Lys37]GLP-1-(7-37);N-epsilon37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino]butyrylamino}butyrylamino)ethoxy]ethoxy}acetyl)[DesaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-Butyl-2H-tetrazol-5-yl)-hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl}[DesaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22, Arg26,Arg34,Lys37]GLP-1-(7-37);N-alpha37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7-37)peptide;N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7, Glu22,Arg26,Arg34,Lys37] GLP-1-(7-37);N-epsilon36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7, Glu22,Arg26,Glu30,Arg34,Lys36] GLP-1-(7-37)-Glu-Lyspeptide;N-epsilon37-[2-(2-{2-[2-(2-({2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl-amino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl]-[Aib8,Glu22,Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37);N-epsilon37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoylamino)ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetylamino) butyryl][Aib8,Glu22,Arg26,34,Lys37] GLP-1 (7-37);N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyry-lamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][ImPr7,Glu22, Arg26,34,Lys37], GLP-1-(7-37);N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy] acetylamino}ethoxy)ethoxy]acetyl},N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)decanoylamino] butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH; N-epsilon26(17-carboxyhepta-decanoyl)-[Aib8,Arg34]GLP-1-(7-37)-peptide;N-epsilon26-(19-carboxynonadecanoyl)-[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-(4-{[N-(2-carboxyethyl)-N-(15-carboxypenta-decanoyl)amino]methyl}benzoyl[Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino) ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(19-carboxynonadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][3-(4-Imidazolyl)Propionyl7,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-(carboxymethyl-amino)acetylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-3(S)-Sulfopropionylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)-amide;N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34,Pro37]GLP-1-(7-37)amide;Aib8,Lys26(N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}), Arg34)GLP-1 H(7-37)-OH;N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxyheptadecanoyl)amino]methyl}benzoyl)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37);N-alpha7-formyl,N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxy-butyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Arg34]GLP-1-(7-37);N-epsilon2626-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxy-butyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Glu22, Arg34] GLP-1-(7-37);N-epsilon26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N—((S)-1,3-dicarboxypropyl)carbamoyl)pentadecanoylamino)-(S)-4-carboxybutyrylamino] ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxy-heptadecanoyl)amino]methyl}benzoyl)amino](4(S)-carboxybutyryl-amino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34] GLP-1(7-37);N-epsilon26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino)butyrylamino)butyrylamino)butyrylamino} [Aib8,Arg34]GLP-1-(7-37);N-epsilon26-4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutyryl-[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37);N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,35,Arg34,Pro37,Lys26] GLP-1 (7-37)amide;N-epsilon26-[2-(2-[2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);andN-epsilon26-[2-(2-[2-(2-[2-(2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37).In one embodiment the GLP-1 peptide isN-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy] acetylamino}ethoxy)ethoxy]acetyl},N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)decanoylamino] butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH (Compound A).

In one embodiment the GLP-1 peptide isN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37), also known as semaglutide.

In one embodiment GLP-1 peptides can be produced by appropriatederivatisation of an appropriate peptide backbone which has beenproduced by recombinant DNA technology or by peptide synthesis (e.g.,Merrifield-type solid phase synthesis) as known in the art of peptidesynthesis and peptide chemistry.

In one embodiment the production of peptides like GLP-1(7-37) and GLP-1analogues is well known in the art. The GLP-1 moiety of the GLP-1peptide of the invention (or fragments thereof) may for instance beproduced by classical peptide synthesis, e.g., solid phase peptidesynthesis using t-Boc or Fmoc chemistry or other well establishedtechniques, see, e.g., Greene and Wuts, “Protective Groups in OrganicSynthesis”, John Wiley & Sons, 1999, Florencio Zaragoza Dörwald,“Organic Synthesis on solid Phase”, Wiley-VCH Verlag GmbH, 2000, and“Fmoc Solid Phase Peptide Synthesis”, Edited by W. C. Chan and P. D.White, Oxford University Press, 2000.

In one embodiment GLP-1 peptides may be produced by recombinant methods,viz. by culturing a host cell containing a DNA sequence encoding theGLP-1 peptide and capable of expressing the peptide in a suitablenutrient medium under conditions permitting the expression of thepeptide. Non-limiting examples of host cells suitable for expression ofthese peptides are: Escherichia coli, Saccharomyces cerevisiae, as wellas mammalian BHK or CHO cell lines.

In one embodiment GLP-1 peptides of the invention which includenon-natural amino acids and/or a covalently attached N-terminal mono- ordipeptide mimetic may e.g. be produced as described in the experimentalpart. Or see e.g., Hodgson et al: “The synthesis of peptides andproteins containing non-natural amino acids”, Chemical Society Reviews,vol. 33, no. 7 (2004), p. 422-430; and WO 2009/083549 A1 entitled“Semi-recombinant preparation of GLP-1 analogues”.

Salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid

The delivery agent used in the present invention is a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments thedelivery agent is an absorption enhancer. The structural formula ofN-(8-(2-hydroxybenzoyl)amino)caprylate is shown in formula (I).

In some embodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylicacid is in the caprylic acid form and/or the capraylate form. In someembodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidcomprises one monovalent cation, two monovalent cations or one divalentcation. In some embodiments the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the groupconsisting of the sodium salt, potassium salt and calcium salt of ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid.

Salts of N-(8-(2-hydroxybenzoyl)amino)caprylate may be prepared usingthe method described in e.g. WO96/030036, WO00/046182, WO01/092206 orWO2008/028859.

The salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may becrystalline and/or amorphous. In some embodiments the delivery agentcomprises the anhydrate, monohydrate, dihydrate, trihydrate, a solvateor one third of a hydrate of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid as well as combinations thereof. In some embodiments thedelivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidas described in WO2007/121318. The salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid may be any polymorph thereof.

In some embodiments the delivery agent is sodiumN-(8-(2-hydroxybenzoyl)amino)caprylate (referred to as “SNAC” herein),also known as sodium 8-(salicyloylamino) octanoate.

In some embodiments the amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is in the range of 0.6-3.5 mmol.In some embodiments the amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is at least 0.6 mmol, such asselected from the group at least 0.8 mmol or at least 0.9 mmol. In someembodiments the amount of the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is up to2.5 mmol. In some embodiments the amount of the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is 0.6-2.0mmol. In some embodiments the amount of the salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is 1 mmol, such as 1.08 mmol.

In some embodiments the amount of SNAC in the composition is in therange of 100-1000 mg. In some embodiments the amount of SNAC in thecomposition is at least 150 mg or at least 250 mg. In some embodimentsthe amount of SNAC in the composition is up to 800 mg, such as up to 700mg or up to 600 mg. In some embodiments the amount of SNAC in thecomposition is 300 mg.

In some embodiments the molar ratio between GLP-1 agonist (i.e. GLP-1peptide) and delivery agent in the composition is less than 10, such asless than 5 or less than 1. In some embodiments the molar ratio betweenGLP-1 agonist (i.e. GLP-1 peptide) and delivery agent in the compositionis less than 1/10, such as less than 1/100 or less than 5/1000.

Pharmaceutical Indications

The present invention also relates to a composition or a granule of theinvention for use as a medicament. In one embodiment the composition orthe granule is administered orally.

In particular embodiments, the composition or a granule of the inventionmay be used for the following medical treatments, all preferablyrelating one way or the other to diabetes:

(i) prevention and/or treatment of all forms of diabetes, such ashyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetesof the young), gestational diabetes, and/or for reduction of HbA1C;

(ii) delaying or preventing diabetic disease progression, such asprogression in type 2 diabetes, delaying the progression of impairedglucose tolerance (IGT) to insulin requiring type 2 diabetes, and/ordelaying the progression of non-insulin requiring type 2 diabetes toinsulin requiring type 2 diabetes;

(iii) improving β-cell function, such as decreasing β-cell apoptosis,increasing β-cell function and/or β-cell mass, and/or for restoringglucose sensitivity to β-cells;

(iv) prevention and/or treatment of cognitive disorders;

(v) prevention and/or treatment of eating disorders, such as obesity,e.g. by decreasing food intake, reducing body weight, suppressingappetite, inducing satiety; treating or preventing binge eatingdisorder, bulimia nervosa, and/or obesity induced by administration ofan antipsychotic or a steroid; reduction of gastric motility; and/ordelaying gastric emptying;

(vi) prevention and/or treatment of diabetic complications, such asneuropathy, including peripheral neuropathy; nephropathy; orretinopathy;

(vii) improving lipid parameters, such as prevention and/or treatment ofdyslipidemia, lowering total serum lipids; lowering HDL; lowering small,dense LDL; lowering VLDL: lowering triglycerides; lowering cholesterol;increasing HDL; lowering plasma levels of lipoprotein a (Lp(a)) in ahuman; inhibiting generation of apolipoprotein a (apo(a)) in vitroand/or in vivo;

(iix) prevention and/or treatment of cardiovascular diseases, such assyndrome X; atherosclerosis; myocardial infarction; coronary heartdisease; stroke, cerebral ischemia; an early cardiac or earlycardiovascular disease, such as left ventricular hypertrophy; coronaryartery disease; essential hypertension; acute hypertensive emergency;cardiomyopathy; heart insufficiency; exercise tolerance; chronic heartfailure; arrhythmia; cardiac dysrhythmia; syncopy; atheroschlerosis;mild chronic heart failure; angina pectoris; cardiac bypass reocclusion;intermittent claudication (atheroschlerosis oblitterens); diastolicdysfunction; and/or systolic dysfunction;

(ix) prevention and/or treatment of gastrointestinal diseases, such asinflammatory bowel syndrome; small bowel syndrome, or Crohn's disease;dyspepsia; and/or gastric ulcers;

(x) prevention and/or treatment of critical illness, such as treatmentof a critically ill patient, a critical illness poly-nephropathy (CIPNP)patient, and/or a potential CIPNP patient; prevention of criticalillness or development of CIPNP; prevention, treatment and/or cure ofsystemic inflammatory response syndrome (SIRS) in a patient; and/or forthe prevention or reduction of the likelihood of a patient sufferingfrom bacteraemia, septicaemia, and/or septic shock duringhospitalisation; and/or

(xi) prevention and/or treatment of polycystic ovary syndrome (PCOS).

In a particular embodiment, the indication is selected from the groupconsisting of (i)-(iii) and (v)-(iix), such as indications (i), (ii),and/or (iii); or indication (v), indication (vi), indication (vii),and/or indication (iix).

In another particular embodiment, the indication is (i). In a furtherparticular embodiment the indication is (v). In a still furtherparticular embodiment the indication is (iix).

In one embodiment the invention relates to a composition or a granule ofthe invention for treatment of diabetes or obesity, wherein said granuleis administered orally. In one embodiment the invention relates to amethod for treatment of diabetes or obesity comprising oraladministration of a composition comprising a composition or a granule ofthe invention to a patient in need thereof.

The following indications are particularly preferred: Type 2 diabetes,and/or obesity.

Particular Embodiments

The following are particular embodiments of the invention

1. A pharmaceutical composition comprising a first type and a secondtype of granules, wherein said first type of granules comprises a saltof N-(8-(2-hydroxybenzoyl)amino)caprylic acid, and wherein said secondtype of granules comprises a GLP-1 peptide.

2. A pharmaceutical composition according to any one of the precedingembodiments, wherein said first type of granules does not comprise GLP-1peptide.

3. A pharmaceutical composition according to any one of the precedingembodiments, wherein said second type of granules does not comprise saltof N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

4. A pharmaceutical composition according to any one of the precedingembodiments, wherein said first type of granules further comprises alubricant, such as magnesium stearate.

5. A pharmaceutical composition according to any one of the precedingembodiments, wherein said first type of granules further comprises afiller, such as microcrystalline cellulose.

6. A pharmaceutical composition according to any one of the precedingembodiments, wherein said second type of granules further comprises afiller, such as microcrystalline cellulose.

7. A pharmaceutical composition according to any one of the precedingembodiments, wherein said second type of granules further comprises abinder, such as povidone.

8. A pharmaceutical composition according to any one of the precedingembodiments, wherein the granules are manufactured by dry granulation,such as by roller compaction.

9. A pharmaceutical composition according to any one of the precedingembodiments, wherein the release of said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid is simultaneous with orfaster than the release of said GLP-1 peptide.

10. A pharmaceutical composition according to any one of the precedingembodiments, wherein said the release of said salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and/or said GLP-1 peptide isdetermined by dissolution testing using Assay (I) and wherein saidrelease is optionally determined within 30 minutes of said dissolutiontesting.11. A pharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, whereinthe release of said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidis simultaneous with or faster than the release of said GLP-1 peptide asdetermined by dissolution testing using Assay (I).12. A pharmaceutical composition according to any one of the precedingembodiments, wherein the amount of dissolved salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid peaks within the first 60minutes as determined by dissolution testing using Assay (I) at pH 2.5.13. A pharmaceutical composition according to any one of the precedingembodiments, wherein the amount of dissolved salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid peaks within 55 minutes, suchas within 50, 45, 40, 39, 38, 37, 36, 35, 34, 33, 32, or 31 minutes asdetermined by dissolution testing using Assay (I) at pH 2.5.14. A pharmaceutical composition according to any one of the precedingembodiments, wherein the amount of dissolved salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid peaks within the first 30minutes as determined by dissolution testing using Assay (I) at pH 2.5.15. A pharmaceutical composition according to any one of the precedingembodiments, wherein the amount of dissolved salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid peaks within 31 minutes, suchas within 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, or 60 minutesas determined by dissolution testing using Assay (I) at pH 2.5.16. A pharmaceutical composition according to any one of the precedingembodiments, wherein the amount of dissolved salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid peaks within 30 minutes, suchas within 25, 20, 15, 10, or 5 minutes as determined by dissolutiontesting using Assay (I) at pH 2.5.17. A pharmaceutical composition according to any one of the precedingembodiments, wherein said dissolution testing using Assay (I) is carriedout at any one of pH 1.0-8.0.18. A pharmaceutical composition according to any one of the precedingembodiments, wherein said dissolution testing using Assay (I) is carriedout at pH 1.0.19. A pharmaceutical composition according to any one of the precedingembodiments, wherein said dissolution testing using Assay (I) is carriedout at pH 2.5.20. A pharmaceutical composition according to any one of the precedingembodiments, wherein said dissolution testing using Assay (I) is carriedout at pH 6.8.21. A pharmaceutical composition according to any one of the precedingembodiments, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylicacid is SNAC.22. A pharmaceutical composition according to any one of the precedingembodiments, wherein the GLP-1 peptide comprises an albumin bindingmoiety.23. A pharmaceutical composition according to any one of the precedingembodiments, wherein the GLP-1 peptide isN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37).24. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition further comprises one or morepharmaceutically acceptable excipients.25. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition is in the form of a solid dosageform.26. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition is in the form of a tablet.27. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition is in the form of a capsule.28. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition is in the form of a sachet.29. A pharmaceutical composition according to any one of the precedingembodiments further comprising any combination of the features accordingto embodiments 1-28.30. A process of producing a pharmaceutical composition comprising asalt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide,wherein the process comprises the steps:

-   -   a) mixing a GLP-1 peptide with a filler and/or a binder;    -   b) dry granulation of the mixture of step a;    -   c) mixing the granules obtained in step b with a composition        comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid;        and    -   d) optionally adding further lubricant.        31. A process of producing a pharmaceutical composition        comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        and a GLP-1 peptide, wherein the process comprises the steps:    -   a) mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        with a lubricant and/or a filler;    -   b) dry granulation of the mixture of step a;    -   c) mixing the granules obtained in step b with a composition        comprising a GLP-1 peptide; and    -   d) optionally adding further lubricant.        32. A process of producing a pharmaceutical composition        comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        and a GLP-1 peptide, wherein the process comprises the steps:    -   a) mixing a GLP-1 peptide with a filler and/or a binder;    -   b) dry granulation of the mixture of step a;    -   c) mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid,        optionally a lubricant and/or a filler;    -   d) dry granulation of the mixture of step c;    -   e) mixing the granules obtained in step b with the granules        obtained in step d; and    -   f) optionally adding further lubricant.        33. A process according to any one of embodiments 30-32, wherein        said dry granulation is roller compaction.        34. A process according to any one of embodiments 30-33, wherein        said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.        35. A process according to any one of embodiments 30-34, wherein        said GLP-1 peptide is semaglutide.        36. A process according to any one of embodiments 30-35, wherein        said lubricant and/or said further lubricant is magnesium        stearate.        37. A process according to any one of embodiments 30-36, wherein        said filler is microcrystalline cellulose.        38. A process according to any one of embodiments 30-37, wherein        said binder is povidone.        39. A process according to any one of embodiments 30-38, wherein        said mixing step comprising mixing of a salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant        and/or a filler prior to dry granulation has a duration of at        least 20 minutes, such as at least 30 minutes or at least 40        minutes, such as 50 minutes.        40. A process according to any one of embodiments 30-39, wherein        said mixing comprising mixing of the first type of granules        comprising a GLP-1 peptide with the second type of granules        comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        has a duration of at least 15 minutes or at least 20 minutes,        such as 25 minutes or at least 30 minutes.        41. A pharmaceutical composition obtained by the process as        defined in any one of embodiments 30-40.        42. A pharmaceutical composition as defined in any one of        embodiments 1-29 or 41 for use in medicine.        43. A pharmaceutical composition as defined in any one of        embodiments 1-29 or 41 for treatment of diabetes or obesity.        44. A pharmaceutical composition according to embodiment 42 or        43, wherein said pharmaceutical composition is administered        orally.        45. A method for treatment of diabetes or obesity comprising        administration of a composition comprising the pharmaceutical        composition as defined in any one of embodiments 1-29 or 41 to a        patient in need thereof.        46. A method according to embodiment 45, wherein said        composition is administered orally.        47. A granule comprising a salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a lubricant, and a        filler.        48. A granule comprising a salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant.        49. A granule comprising a GLP-1 peptide, a filler and a binder.        50. A granule according to any one of embodiments 47-49, wherein        said lubricant is magnesium stearate.        51. A granule according to any one of embodiments 47-50, wherein        said filler is microcrystalline cellulose.        52. A granule according to any one of embodiments 47-51, wherein        said binder is povidone.        53. A granule according to any one of embodiments 47-52, wherein        said granule is prepared according to the process as defined in        any one of embodiments 30-40.        54. A process of producing a granule comprising a salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid, wherein the process        comprises the steps:    -   a) mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        (such as SNAC) with a lubricant and/or a filler; and    -   b) dry granulation of the mixture of step a.        55. A process according to embodiment 54, wherein said salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.        56. A process according to embodiment 54 or 55, wherein said        lubricant is magnesium stearate.        57. A process according to any one of embodiments 54-56, wherein        said mixing step comprising mixing of a salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant        and/or a filler prior to dry granulation has a duration of at        least 20 minutes, such as at least 30 minutes or at least 40        minutes, such as 50 minutes.        58. A process of producing a granule comprising a GLP-1 peptide,        wherein the process comprises the steps:    -   a) mixing a GLP-1 peptide, optionally a filler and/or a binder;        and    -   b) roller compacting the mixture of step a.        59. A process according to embodiment 58, wherein said GLP-1        peptide is semaglutide.        60. A process according to any one of embodiments 58-59, wherein        said binder is povidone.        61. A process according to any one of embodiments 58-60, wherein        said filler is microcrystalline cellulose.        62. A process according to any one of embodiments 58-61, wherein        said dry granulation is roller compaction.        63. A granule obtained by the process as defined in any one of        embodiments 58-62.        64. A method for increasing oral bioavailability of a GLP-1        peptide comprising administration to a patient in need thereof        of a composition as defined in any of embodiments 1-29 or 41.        65. A pharmaceutical composition according to any one of the        preceding embodiments wherein said simultaneous or faster        release is determined within 30 minutes, such as within 25, 20,        15 or 10 minutes, as determined by dissolution testing using        Assay (I).        66. A pharmaceutical composition according to any one of the        preceding embodiments wherein said simultaneous or faster        release is determined within 30 minutes, such as within 25, 20,        15 or 10 minutes, as determined by dissolution testing using        Assay (I) at pH 2.5.

Further Particular Embodiments

The following are further particular embodiments of the invention:

1. A pharmaceutical composition comprising a salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, whereinthe release of said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acidis simultaneous with or faster than the release of said GLP-1 peptide asdetermined by dissolution testing using Assay (I).2. A pharmaceutical composition according to any one of the precedingembodiments, wherein the amount of dissolved salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid peaks within the first 30minutes as determined by dissolution testing using Assay (I) at pH 2.5.3. A pharmaceutical composition according to any one of the precedingembodiments, wherein the amount of dissolved salt ofN-(8-(2-hydroxybenzoyl)amino)caprylic acid peaks within 31 minutes, suchas within 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, or 60 minutesas determined by dissolution testing using Assay (I) at pH 2.5.4. A pharmaceutical composition according to any one of the precedingembodiments, wherein said dissolution testing using Assay (I) is carriedout at any one of pH 1.0-8.0.5. A pharmaceutical composition according to any one of the precedingembodiments, wherein said dissolution testing using Assay (I) is carriedout at pH 1.0.6. A pharmaceutical composition according to any one of the precedingembodiments, wherein said dissolution testing using Assay (I) is carriedout at pH 2.5.7. A pharmaceutical composition according to any one of the precedingembodiments, wherein said dissolution testing using Assay (I) is carriedout at pH 6.8.8. A pharmaceutical composition according to any one of the precedingembodiments, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylicacid is SNAC.9. A pharmaceutical composition according to any one of the precedingembodiments, wherein the GLP-1 peptide comprises an albumin bindingmoiety.10. A pharmaceutical composition according to any one of the precedingembodiments, wherein the GLP-1 peptide isN-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37).11. A pharmaceutical composition comprising a first type and a secondtype of granules, wherein said first type of granules comprises a saltof N-(8-(2-hydroxybenzoyl)amino)caprylic acid and said second type ofgranules comprises a GLP-1 peptide.12. A pharmaceutical composition according to embodiment 11, whereinsaid first type of granules further comprises a lubricant, such asmagnesium stearate.13. A pharmaceutical composition according to embodiment 11 or 12,wherein said first type of granules further comprises a filler, such asmicrocrystalline cellulose.14. A pharmaceutical composition according to any one of embodiments11-13, wherein said second type of granules further comprises a filler,such as microcrystalline cellulose.15. A pharmaceutical composition according to any one of embodiments11-14, wherein said second type of granules further comprises a binder,such as povidone.16. A pharmaceutical composition according to any one of embodiments11-15, wherein the granules are manufactured by dry granulation, such asby roller compaction.17. A pharmaceutical composition according to any one of embodiments11-16 further comprising any combination of the features according toembodiments 1-10.18. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition further comprises one or morepharmaceutically acceptable excipients.19. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition is in the form of a solid dosageform.20. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition is in the form of a tablet.21. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition is in the form of a capsule.22. A pharmaceutical composition according to any one of the precedingembodiments, wherein said composition is in the form of a sachet.23. A process of producing a pharmaceutical composition comprising asalt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide,wherein the process comprises the steps:

-   -   a) mixing a GLP-1 peptide with a filler and/or a binder;    -   b) dry granulation of the mixture of step a;    -   c) mixing the granules obtained in step b with a composition        comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid;        and    -   d) optionally adding further lubricant.        24. A process of producing a pharmaceutical composition        comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        and a GLP-1 peptide, wherein the process comprises the steps:    -   a) mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        with a lubricant and/or a filler;    -   b) dry granulation of the mixture of step a;    -   c) mixing the granules obtained in step b with a composition        comprising a GLP-1 peptide; and    -   d) optionally adding further lubricant.        25. A process of producing a pharmaceutical composition        comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        and a GLP-1 peptide, wherein the process comprises the steps:    -   a) mixing a GLP-1 peptide with a filler and/or a binder;    -   b) dry granulation of the mixture of step a;    -   c) mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid,        optionally a lubricant and/or a filler;    -   d) dry granulation of the mixture of step c;    -   e) mixing the granules obtained in step b with the granules        obtained in step d; and    -   f) optionally adding further lubricant.        26. A process according to any one of embodiments 23-25, wherein        said dry granulation is roller compaction.        27. A process according to any one of embodiments 23-26, wherein        said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.        28. A process according to any one of embodiments 23-27, wherein        said GLP-1 peptide is semaglutide.        29. A process according to any one of embodiments 23-28, wherein        said lubricant and/or said further lubricant is magnesium        stearate.        30. A process according to any one of embodiments 23-29, wherein        said filler is microcrystalline cellulose.        31. A process according to any one of embodiments 23-30, wherein        said binder is povidone.        32. A process according to any one of embodiments 23-31, wherein        said mixing step comprising mixing of a salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant        and/or a filler prior to dry granulation has a duration of at        least 30 minutes or at least 40 minutes, such as 50 minutes.        33. A process according to any one of embodiments 23-32, wherein        said mixing comprising mixing of the first type of granules        comprising a GLP-1 peptide with the second type of granules        comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        has a duration of at least 15 minutes or at least 20 minutes,        such as 25 minutes.        34. A pharmaceutical composition obtained by the process as        defined in any one of embodiments 23-33.        35. A pharmaceutical composition as defined in any one of        embodiments 1-22 or 34 for use in medicine.        36. A pharmaceutical composition as defined in any one of        embodiments 1-22 or 34 for treatment of diabetes or obesity.        37. A pharmaceutical composition according to embodiment 35 or        36, wherein said pharmaceutical composition is administered        orally.        38. A method for treatment of diabetes or obesity comprising        administration of a composition comprising the pharmaceutical        composition as defined in any one of embodiments 1-22 or 34 to a        patient in need thereof.        39. A method according to embodiment 38, wherein said        composition is administered orally.        40. A granule comprising a salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a lubricant, and a        filler.        41. A granule comprising a salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant.        42. A granule comprising a GLP-1 peptide, a filler and a binder.        43. A granule according to any one of embodiments 40-42, wherein        said lubricant is magnesium stearate.        44. A granule according to any one of embodiments 40-43, wherein        said filler is microcrystalline cellulose.        45. A granule according to any one of embodiments 40-44, wherein        said binder is povidone.        46. A granule according to any one of embodiments 40-45, wherein        said granule is prepared according to the process as defined in        any one of embodiments 23-34.        47. A process of producing a granule comprising a salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid, wherein the process        comprises the steps:    -   a) mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid        (such as SNAC) with a lubricant and/or a filler; and    -   b) dry granulation of the mixture of step a.        48. A process according to embodiment 47, wherein said salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.        49. A process according to embodiment 47 or 48, wherein said        lubricant is magnesium stearate.        50. A process according to any one of embodiments 47-49, wherein        said mixing step comprising mixing of a salt of        N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant        and/or a filler prior to dry granulation has a duration of at        least 30 minutes or at least 40 minutes, such as 50 minutes.        51. A process of producing a granule comprising a GLP-1 peptide,        wherein the process comprises the steps:    -   a) mixing a GLP-1 peptide, optionally a filler and/or a binder;        and    -   b) roller compacting the mixture of step a.        52. A process according to embodiment 51, wherein said GLP-1        peptide is semaglutide.        53. A process according to any one of embodiments 51-52, wherein        said binder is povidone.        54. A process according to any one of embodiments 47-53, wherein        said filler is microcrystalline cellulose.        55. A process according to any one of embodiments 47-54, wherein        said dry granulation is roller compaction.        56. A granule obtained by the process as defined in any one of        embodiments 47-55.        57. A granule as defined in any one of embodiments 40-46 or 56        for use in medicine.        58. A granule as defined in any one of embodiments 40-46 or 56        for treatment of diabetes or obesity.        59. A granule according to embodiment 57 or 58, wherein said        granule is administered orally in a pharmaceutical composition.        60. A method for treatment of diabetes or obesity comprising        oral administration of a pharmaceutical composition comprising        the granule as defined in any one of embodiments 40-46 or 56 to        a patient in need thereof.        61. A method according to embodiment 60, wherein said        pharmaceutical composition is administered orally.

EXAMPLES

Materials and Methods

General Methods of Preparation

Dry Granulation

Dry granulation was carried out by roller compaction on a GerteisMINI-PACTOR using smooth rolls and the settings listed in Table 1.

TABLE 1 Settings for dry granulation on the roller compactor ParameterSetting Agitator speed 5.0 rpm Roll speed 1.5 or 3.0 rpm Gap 1.0 mmForce 5.0 or 6.0 kN/cm Granulator screen 0.63 mm wire screen Granulatorspeed 60 rpm

Roller compaction force, i.e. the force between the rolls of the rollercompactor when compacting materials into a continuous strip ofcompressed material, was determined by a pressure transducer thatconverts the hydraulic pressure into electrical signal; the rollercompaction force may be measured in kiloNewton (kN) or in kiloNewton perroll width (kN/cm).

Subsequent to dry granulation comminution of the moldings into granuleswas carried out.

Tablet Preparation

Tablets were produced on a Korsch PH106 or a Fette 102i mounted with agravity feeder and a single set of punches resulting in 13 mm×7.5 mmconvex oval tablets having no score. The press speed of the Korsch PH106was set around 25 rpm and the counter pressure was adjusted to 40 kN.The press speed of the Fette 102i was set around 20 rpm. The fill volumewas adjusted to obtain tablets having a target weight 407.7 mg. Thecompression force was set to obtain tablets with a crushing strength ofaround 180±20 N for the Korsch PH106 and of around 128 N for the Fette102i.

Resistance to Crushing of Tablets

Resistance to crushing of tablets was determined according to section2.9.8 in the European Pharmacopoeia 7.5, 7th edition 2012 and at a jawspeed of 20 N/s.

General Methods of Detection and Characterisation

Assay (I): Dissolution Testing

The dissolution test was conducted with apparatus 2 in accordance withUnited States Pharmacopoeia 35 using a paddle rotation speed of 50 rpm.For testing at pH 1.0, 2.5 or 6.8, the 500 mL dissolution medium of 0.1N hydrochloric acid (pH 1.0), 0.05 M phthalate buffer (pH 2.5), or 0.05M phosphate buffer (pH 6.8), respectively, was used at a temperature of37° C. All dissolution media had a content of 0.1% Tween80. Samplealiquots were removed at appropriate intervals and samples with acidicmedium were neutralized with tribasic sodium phosphate to preventprecipitation. Sample contents were determined using a RP-HPLC methodfor dual detection of SNAC and GLP-1 (e.g. semaglutide) The HPLC methodwas based on gradient elution on a C8 column. The solvent system wastrifluoroacetic acid and acetonitrile with UV detection at 210 and 335nm. The sample contents were calculated based on the peak area of theSNAC and GLP-1 (e.g. semaglutide) peaks in the chromatogram relative tothe peak areas of the SNAC and GLP-1 (e.g. semaglutide) references,respectively. The released amounts of SNAC and GLP-1 (e.g. semaglutide)were calculated as percentages of the nominal contents in the tableti.e. 300 mg/tablet SNAC and 10 mg/tablet GLP-1 (e.g. semaglutide) andthen optionally corrected for the actual contents in the tablets. Theactual contents in the tablets were determined using Assay (III).Assay(II):

Bioavailability in Dogs

Animals, Dosing and Blood Sampling: Male and female beagle dogs,weighing approx. 6-22 kg during the study period, were included in thestudy. The dogs were dosed in fasting state and the dogs were fedapprox. 4 hours post dosing. The formulations were administered by oraladministration to the dogs in groups of typically 8 (such as 4 male and4 females).

The bioavailability studies were conducted either as single dose (SD)studies or multiple dose (MD) studies. In the MD studies the formulationwas administered with five consecutive dosing occasions in each study(once a day dosing).

Blood samples were taken to cover the pharmacokinetic profile. Anexample of a SD blood sampling regimen could be the following timepoints: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48,72, 96, 120, 144, 192 and 240 hours post dosing. An example of a MDblood sampling regimen could be the following time points: pre-dose,0.5, 1.5 and 3 hr post dosing after each dosing occasion and a bloodsampling regimen equivalent to a SD blood sampling regimen following thelast dosing occasion.

Preparation of Plasma: All blood samples were collected into test tubescontaining EDTA for stabilisation and kept on ice until centrifugation.Plasma was separated from whole blood by centrifugation and the plasmawas stored at −20° C. or lower until analysis.

Analysis of Plasma Samples: The plasma was analysed for semaglutideusing a Luminescence Oxygen Channeling Immunoassay (LOCI). The LOCIassay employs donor beads coated with streptavidin and acceptor beadsconjugated with a monoclonal antibody binding to a mid-molecular regionof GLP-1 (e.g. semaglutide). The other monoclonal antibody, specific foran N-terminal epitope, was biotinylated. In the assay the threereactants were combined with the GLP-1 (e.g. semaglutide) which form atwo-sited immuno-complex. Illumination of the complex releases singletoxygen atoms from the donor beads which channels into the acceptor beadsand trigger chemiluminescence which was measured in the EnVision platereader. The amount of light was proportional to the concentration ofsemaglutide and the lower limit of quantification (LLOQ) in plasma was100 pM.

Pharmacokinetic Calculations: GLP-1 (e.g. semaglutide) plasmaconcentration data were subjected to non-compartmental pharmacokineticanalysis using the PC based software WinNonlin, v. 5.2 or later(Pharsight, Mountain View, Calif. 94041, USA). For each individual dogthe following pharmacokinetic parameters were estimated: Area Under theCurve (AUC), and dose normalized AUC (AUC/D). Bioavailability (F) wascalculated as the fraction absorbed (in %) based on the dose normalisedAUC (AUCinf./D) following oral and intravenous administration. Summarystatistics of pharmacokinetic results were presented as arithmetic mean.

Assay (III): Analysis of Amount of GLP-1 and SNAG

For assay analysis tablets were dissolved using 0.05 M Na₂HPO₄ with0.01% Tween20 as extraction buffer. Sample content was determined usinga RP-HPLC method for dual detection of SNAC and GLP-1 (e.g.semaglutide). The HPLC method was based on gradient elution on a C8column. The solvent system was trifluoroacetic acid and acetonitrilewith UV detection at 210 and 335 nm. The sample contents were calculatedbased on the peak area of the SNAC and GLP-1 (e.g. semaglutide) peaks inthe chromatogram relative to the peak areas of the SNAC and GLP-1 (e.g.semaglutide) references, respectively. The content was reported asaverage of 10 tablets.

Example 1 Preparation of Tablet Compositions Comprising GLP-1 and SNAC

Tablet compositions comprising GLP-1 and SNAC were prepared with thecomponents shown in Table 2. Compound A isN-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy] acetylamino}ethoxy)ethoxy]acetyl},N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy-phenoxy)decanoylamino] butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH.

TABLE 2 Composition of the tablet compositions Component Amount(mg/tablet) Function Semaglutide or Compound A 10 Active ingredient SNAC300 Delivery agent Microcrystalline cellulose 80 Filler (Avicel PH 101)Povidone K 90 (Kollidon 90F) 8 Binder Magnesium stearate 9.7 LubricantTotal amount 407.7

Tablet compositions were prepared by mixing the components listed inTable 2 in different ways. The tablet compositions consisted of a firsttype of granules, in some cases a second type of granules, as well asextragranular ingredients mixed with the first type of granules and, ifpresent, the second type of granules. Preparation of granules by rollercompaction and preparation of tablets from the tablet compositions wereas described in the section General Methods of Preparation. The designof the tablet compositions is shown in Table 3.

TABLE 3 Design of tablet compositions (the amount of each component inmg/tablet is shown in brackets) Composition of Composition of Tabletfirst type of second type of Extragranular compo- granules granulesingredients sition (mg/tablet) (mg/tablet) (mg/tablet) B SNAC (300),semaglutide (10), magnesium magnesium microcrystalline stearate (2)stearate (7.7) cellulose (80), povidone (8) C SNAC (300), —microcrystalline semaglutide (10), cellulose (80), magnesium povidone(8), stearate (7.7) magnesium stearate (2) D SNAC (300), —microcrystalline semaglutide (10), cellulose (80), povidone (8),magnesium magnesium stearate (2) stearate (7.7) E SNAC (300), —magnesium semaglutide (10), stearate (2) microcrystalline cellulose(80), povidone (8), magnesium stearate (7.7) F SNAC (300), semaglutide(10), magnesium microcrystalline microcrystalline stearate (2) cellulose(57), cellulose (23), magnesium povidone (8) stearate (7.7) G SNAC(300), Compound A (10), magnesium magnesium microcrystalline stearate(2) stearate (7.7) cellulose (80), povidone (8) H SNAC (300), Compound A(10), magnesium microcrystalline microcrystalline stearate (2) cellulose(57), cellulose (23), magnesium povidone (8) stearate (7.7)Further details of the preparation of the tablet compositions areprovided below.Tablet Composition B

Magnesium stearate for the first granule fraction was passed through a355 μm sieve. Magnesium stearate was manually mixed with SNAC in astainless steel bowl in corresponding volumes. Two cycles of geometricdilution was applied by mixing for around 60 s until the blend wasvisually homogenous. The remaining quantity of SNAC was transferred to ablender and was pre-mixed for 2 min at 25 rpm. The SNAC and magnesiumstearate pre-mix was added to the blender and mixing was performed for20 min at 25 rpm. The blend was roller compacted. The granules weresieved through a 180 μm mesh.

Semaglutide, microcrystalline cellulose and povidone for the secondgranule fraction were weighed directly into a stainless steel bowl inthe order of decreasing amounts and mixed manually for at least 3 minuntil visually homogenous before transferring the pre-mix to a 1000 mLDuma bottle. The Duma bottle was closed with a lid and tumbled manuallyin a Turbula-like movement for 1 min. The blend was roller compacted.

The two types of granules were added to a blending container in order ofdecreasing content and mixed for 5 minutes at 32 rpm. Extragranularmagnesium stearate was mixed with the granule blend by manual mixingusing volume-doubling followed by 30 s mixing in the Turbula mixer at 32rpm. Tablets were prepared from this composition.

Tablet Composition C

Magnesium stearate for the granule fraction was passed through a 355 μmsieve. Magnesium stearate was manually mixed with SNAC in a stainlesssteel bowl in corresponding volumes. Two cycles of geometric dilutionwas applied by mixing for around 60 s until the blend was visuallyhomogenous. The remaining quantity of SNAC was transferred to a blenderand was pre-mixed for 2 min at 25 rpm. The SNAC and magnesium stearatepre-mix was added to the blender and mixing was performed for 20 min at25 rpm. Semaglutide was geometrically diluted using the mixed SNAC andmagnesium stearate from the blender by mixing it manually for at least60 s until visually homogenous. The pre-mix was then added to the mixedSNAC and magnesium stearate. The mixing step was finalized by mixing inthe blender for 10 min at 25 rpm. The blend was roller compacted.

The granules and all other constituents except extragranular magnesiumstearate were added to a blending container in order of decreasingcontent and mixed for 5 minutes at 32 rpm. Extragranular magnesiumstearate was mixed with the granule blend by manual mixing usingvolume-doubling followed by 30 s mixing in the Turbula mixer at 32 rpm.Tablets were prepared from this composition.

Tablet Composition D

Magnesium stearate for the granule fraction was passed through a 355 μmsieve. Magnesium stearate was manually mixed with SNAC in a stainlesssteel bowl in corresponding volumes. Two cycles of geometric dilutionwas applied by mixing for around 60 s until the blend was visuallyhomogenous. The remaining quantity of SNAC was transferred to a blenderand was pre-mixed for 2 min at 25 rpm. The SNAC and magnesium stearatepre-mix was added to the blender and mixing was performed for 20 min at25 rpm. Semaglutide and povidone were weighed into a stainless steelbowl in the order of decreasing amounts and the components were mixedmanually until visually homogenous. A geometric dilution was thenperformed using the mixed SNAC and magnesium stearate from the blenderby mixing it manually for at least 60 s until visually homogenous. Thepre-mix was then added to the mixed SNAC and magnesium stearate. Themixing step was finalized in the blender by mixing for 10 min at 25 rpm.The blend was roller compacted.

The granules and microcrystalline cellulose were added to a blendingcontainer in order of decreasing content and mixed for 5 minutes at 32rpm. Extragranular magnesium stearate was mixed with the granule blendby manual mixing using volume-doubling followed by 30 s mixing in theTurbula mixer at 32 rpm. Tablets were prepared from this composition.

Tablet Composition E

Magnesium stearate for the granule fraction was passed through a 355 μmsieve. Magnesium stearate was manually mixed with SNAC in a stainlesssteel bowl in corresponding volumes. Two cycles of geometric dilutionwas applied by mixing for around 60 s until the blend was visuallyhomogenous. The remaining quantity of SNAC was transferred to a blenderand was pre-mixed for 2 min at 25 rpm. The SNAC and magnesium stearatepre-mix was added to the blender and mixing was performed for 20 min at25 rpm. Semaglutide, microcrystalline cellulose and povidone wereweighed into a stainless steel bowl in the order of decreasing amountsand the components were mixed manually until visually homogenous. Ageometric dilution was then performed using the mixed SNAC and magnesiumstearate from the blender by mixing it manually for at least 60 s untilvisually homogenous. The pre-mix was then added to the mixed SNAC andmagnesium stearate. The mixing step was finalized in the blender bymixing for 10 min at 25 rpm. The blend was roller compacted.

Extragranular magnesium stearate was mixed with the granules by manualmixing using volume-doubling followed by 30 s mixing in the Turbulamixer at 32 rpm. Tablets were prepared from this composition.

Tablet Composition F

Magnesium stearate for granule fraction one was passed through a 355 μmsieve. Magnesium stearate was manually mixed with SNAC in a stainlesssteel bowl in corresponding volumes. Two cycles of geometric dilutionwas applied by mixing for around 60 s until the blend was visuallyhomogenous. The remaining quantity of SNAC was transferred to a blenderand was pre-mixed for 2 min at 25 rpm. The SNAC and magnesium stearatepre-mix was added to the blender and mixing was performed for 20 min at25 rpm. Microcrystalline cellulose was geometrically diluted using themixed SNAC and magnesium stearate from the blender by mixing it manuallyfor at least 60 s until visually homogenous. The pre-mix was then addedto the mixed SNAC and magnesium stearate. The mixing step was finalizedby mixing in the blender for 10 min at 25 rpm. The blend was rollercompacted.

Semaglutide, microcrystalline cellulose (Avicel PH 101, FMC Biopolymer)and povidone (Kollidon 90F, BASF) for granule fraction two were weigheddirectly into a stainless steel bowl in the order of decreasing amountsand mixed manually for at least 3 min until visually homogenous beforetransferring the pre-mix to a 500 mL Duma bottle. The Duma bottle wasclosed with a lid and tumbled manually in a Turbula-like movement for 1min. The blend was roller compacted.

The two types of granules were added to a blending container in order ofdecreasing content and mixed for 5 minutes at 32 rpm. Extragranularmagnesium stearate was mixed with the granule blend by manual mixingusing volume-doubling followed by 30 s mixing in the Turbula mixer at 32rpm. Tablets were prepared from this composition.

Tablet Composition G

Magnesium stearate for the first granule fraction was passed through a355 μm sieve. Magnesium stearate was manually mixed with SNAC in aplastic bag in corresponding volumes. Two cycles of geometric dilutionwas applied by mixing for around 60 s. The SNAC and magnesium stearatepre-mix was added to the blender followed by the addition of theremaining SNAC and mixing was performed for 50 min at 25 rpm. The blendwas roller compacted. The granules were sieved through a 1000 and 90 μmmesh.

Compound A, microcrystalline cellulose and povidone for the secondgranule fraction were weighed directly into a stainless steel bowl inthe order of decreasing amounts and mixed manually for at least 3 minuntil visually homogenous before transferring the pre-mix to a 500 mLDuma bottle. The Duma bottle was closed with a lid and tumbled manuallyin a Turbula-like movement for 3 min. The blend was roller compacted.

The two types of granules were added to a blending container and mixedfor 20 minutes at 25 rpm. Extragranular magnesium stearate was passedthrough a 355 μm sieve and mixed with the granule blend by manual mixingusing volume-doubling followed by 2 min mixing in the Turbula mixer at25 rpm. Tablets were prepared from this composition.

Tablet Composition H

Magnesium stearate for granule fraction one was passed through a 355 μmsieve. Magnesium stearate was manually mixed with SNAC in a plastic bagin corresponding volumes. Two cycles of geometric dilution was appliedby mixing for around 60 s. The SNAC and magnesium stearate pre-mix wasadded to the blender followed by the addition of the remaining SNAC andmixing was performed for 50 min at 25 rpm. Microcrystalline cellulosewas then added to the mixed SNAC and magnesium stearate and the mixingstep was finalized by mixing in the blender for 20 min at 25 rpm. Theblend was roller compacted.

Compound A, microcrystalline cellulose (Avicel PH 101, FMC Biopolymer)and povidone (Kollidon 90F, BASF) for granule fraction two were weigheddirectly into a stainless steel bowl in the order of decreasing amountsand mixed manually for at least 3 min until visually homogenous beforetransferring the pre-mix to a 500 mL Duma bottle. The Duma bottle wasclosed with a lid and tumbled manually in a Turbula-like movement for atleast 3 min. The blend was roller compacted.

The two types of granules were added to a blending container and mixedfor 20 minutes at 25 rpm. Extragranular magnesium stearate was passedthrough a 355 μm sieve and mixed with the granule blend by manual mixingusing volume-doubling followed by 2 minutes mixing in the Turbula mixerat 25 rpm. Tablets were prepared from this composition.

Example 2 Dissolution of GLP-1 and SNAC from Tablet Composition B

The dissolution of semaglutide and SNAC from tablet composition B wasdetermined using Assay (I) described herein. The results are shown inTable 4. Corrected results are adjusted for the content of semaglutideor SNAC determined by analysis using Assay (III) described herein. Thecorrected results show that SNAC is released faster than semaglutideduring the initial 20 min of dissolution. Furthermore, it shows that thedifference between the faster release of SNAC compared to semaglutide isthe largest in the dissolution medium with the pH-value of 2.5. Lastly,the data shows that in dissolution media with pH-values of 1.0 and 2.5the amount of dissolved SNAC peaks within the initial 45 and 30 min,respectively.

TABLE 4 Dissolution of semaglutide and SNAC from tablet composition B pHof dissolution media 1.0 2.5 6.8 Dissolution Semaglutide SNACSemaglutide SNAC Semaglutide SNAC time released released releasedreleased released released (min) (% of total) (% of total) (% of total)(% of total) (% of total) (% of total) 0  0  0  0  0 0 0 0 0  0  0  0  05 — — — — 8 9 19 19 — — — — 10  9 10 13 13 17 18 28 28 — — — — 15 — — —— 22 24 32 32 45 49 53 52 20 17 18 19 19 27 29 34 34 — — — — 30 20 22 2020 35 38 33 33 74 81 81 80 45 23 25 20 20 42 46 30 30 86 94 92 91 60 2426 19 19 46 50 28 28 92 100  96 95 Corrected Yes No Yes No Yes No Yes NoYes No Yes No for actual content

Example 3 Dissolution of GLP-1 and SNAC from Tablet Composition C

The dissolution of semaglutide and SNAC from tablet composition C wasdetermined using Assay (I) described herein. The results are shown inTable 5. The results show that SNAC is released slower than semaglutideafter the initial 5 min of dissolution in the dissolution media with lowpH-values of 1.0 and 2.5. Corrected results are adjusted for the contentof semaglutide or SNAC determined by analysis using Assay (III)described herein. During the initial 5 min of corrected dissolution inthe dissolution medium with the pH-value of 2.5 SNAC is released equallyfast as semaglutide. Furthermore, the corrected dissolution values showthat SNAC is released faster than semaglutide in the dissolution mediumwith the pH-value of 6.8.

TABLE 5 Dissolution of semaglutide and SNAC from tablet composition C pHof dissolution media 1.0 2.5 6.8 Dissolution Semaglutide SNACSemaglutide SNAC Semaglutide SNAC time released released releasedreleased released released (min) (% of total) (% of total) (% of total)(% of total) (% of total) (% of total) 0  0  0  0  0 0 0 0 0  0  0  0  05 — — — — 11 12 11 11 — — — — 10 14 16 11 11 20 22 19 19 — — — — 15 — —— — 24 27 23 23 45 50 48 47 20 23 25 16 16 28 31 25 25 — — — — 30 27 3018 18 34 38 28 28 77 85 80 79 45 30 33 19 19 41 46 29 29 88 98 93 91 6031 34 18 18 46 51 27 27 94 104  99 97 Corrected Yes No Yes No Yes No YesNo Yes No Yes No for actual content

Example 4 Dissolution of GLP-1 and SNAC from Tablet Composition D

The dissolution of semaglutide and SNAC from tablet composition D wasdetermined using Assay (I) described herein. The results are shown inTable 6. The results show that SNAC is released slower than semaglutideafter the initial 5 min of dissolution in the dissolution media with lowpH-values of 1.0 and 2.5. Corrected results are adjusted for the contentof semaglutide or SNAC determined by analysis using Assay (III)described herein. During the initial 5 min of corrected dissolution inthe dissolution medium with the pH-value of 2.5 SNAC is released equallyfast with semaglutide. Furthermore, the corrected dissolution valuesshow that SNAC is released faster than semaglutide in the dissolutionmedium with the pH-value of 6.8.

TABLE 6 Dissolution of semaglutide and SNAC from tablet composition D pHof dissolution media 1.0 2.5 6.8 Dissolution Semaglutide SNACSemaglutide SNAC Semaglutide SNAC time released released releasedreleased released released (min) (% of total) (% of total) (% of total)(% of total) (% of total) (% of total) 0  0  0  0  0 0 0 0 0  0  0  0  05 — — — — 11 12 11 11 — — — — 10 10 11  8  8 17 19 16 16 — — — — 15 — —— — 21 23 19 19 33 37 35 35 20 17 19 12 12 23 26 20 20 — — — — 30 23 2615 15 28 31 22 22 59 66 62 62 45 26 29 16 16 33 37 24 24 75 83 77 77 6027 30 15 15 38 42 25 25 82 91 84 84 Corrected Yes No Yes No Yes No YesNo Yes No Yes No for actual content

Example 5 Dissolution of GLP-1 and SNAC from Tablet Composition E

The dissolution of semaglutide and SNAC from tablet composition E wasdetermined using Assay (I) described herein. The results are shown inTable 7. Corrected results are adjusted for the content of semaglutideor SNAC determined by analysis using Assay (III) described herein. Theresults show that SNAC is released slower than semaglutide during theentire dissolution time in a dissolution medium with a pH-value of 1.0.In a dissolution media with a pH-value of 2.5 the results show that SNACinitially is released faster than semaglutide during the initial 10 to15 min of dissolution before becoming slower. Furthermore, the datashows that in dissolution medium with a pH-value of 2.5 the amount ofdissolved SNAC peaks within the initial 20 min. Lastly, the correcteddissolution values show that SNAC is released faster than semaglutide inthe dissolution medium with the pH-value of 6.8.

TABLE 7 Dissolution of semaglutide and SNAC from tablet composition E pHof dissolution media 1.0 2.5 6.8 Dissolution Semaglutide SNACSemaglutide SNAC Semaglutide SNAC time released released releasedreleased released released (min) (% of total) (% of total) (% of total)(% of total) (% of total) (% of total) 0  0  0  0  0 0 0 0 0  0  0  0 5— — — — 21 23 22 22 — — — — 10 15 17 12 12 38 42 40 40 — — — — 15 — — —— 50 56 46 46 47 53 51 51 20 23 26 16 16 57 64 43 43 — — — — 30 28 31 1616 63 71 37 37 76 85 79 79 45 32 36 17 17 68 76 31 31 86 96 89 89 60 3640 17 17 70 78 28 28 90 101  93 93 Corrected Yes No Yes No Yes No Yes NoYes No Yes No for actual content

Example 6 Dissolution of GLP-1 and SNAC from Tablet Composition F

The dissolution of semaglutide and SNAC from tablet composition F wasdetermined using Assay (I) described herein. The results are shown inTable 8. Corrected results are adjusted for the content of semaglutideor SNAC determined by analysis using Assay (III) described herein. Thecorrected results show that SNAC is released faster than semaglutideduring the initial 20 to 30 min of dissolution. Furthermore, it showsthat the difference between the faster release of SNAC compared tosemaglutide is the largest in the dissolution medium with the pH-valueof 2.5. Lastly, the data shows that in a dissolution medium with apH-value of 2.5 the amount of dissolved SNAC peaks within the initial 30min.

TABLE 8 Dissolution of semaglutide and SNAC from tablet composition F pHof dissolution media 1.0 2.5 6.8 Dissolution Semaglutide SNACSemaglutide SNAC Semaglutide SNAC time released released releasedreleased released released (min) (% of total) (% of total) (% of total)(% of total) (% of total) (% of total) 0  0  0  0  0 0 0 0 0  0  0  0  05 — — — — 9 10 17 17 — — — — 10  8  9 10 10 20 22 31 31 — — — — 15 — — —— 28 31 40 40 51 56 56 56 20 12 13 13 13 33 36 43 43 — — — — 30 15 17 1515 38 42 42 42 75 82 79 79 45 19 21 16 16 43 47 39 39 85 93 88 88 60 2123 16 16 48 53 38 38 89 98 93 93 Corrected Yes No Yes No Yes No Yes NoYes No Yes No for actual content

Example 7 Bioavailability of GLP-1 in Dogs from Tablet Compositions B-F

Bioavailability of GLP-1 from tablet compositions B-F was determined indogs according to Assay (II) described herein. The results are shown inTable 9.

TABLE 9 Bioavailability of GLP-1 in dogs from tablet compositions B-FBioavailability of GLP-1 in dogs Tablet composition (% F) B 0.7 C 0.5 D0.3 E 0.4 F 1.0

The results show that tablet composition F provided a bioavailability of1.0%. The results show that tablet composition B provided abioavailability of 0.7%. The results show that tablet composition Cprovided a bioavailability of 0.5%. The results show that tabletcomposition E provided a bioavailability of 0.4%. The results show thattablet composition D provided a bioavailability of 0.3%.

Example 8 Dissolution of GLP-1 and SNAC from Tablet Composition G

The dissolution of Compound A and SNAC from tablet composition G wasdetermined using Assay (I) described herein. The results are shown inTable 10. The results show that SNAC is released faster than Compound Aduring the initial 20 min of dissolution. Furthermore, it shows that thedifference between the faster release of SNAC compared to Compound A isthe largest in the dissolution medium with the pH-value of 2.5. Lastly,the data shows that in dissolution media with pH-value of 2.5 the amountof dissolved SNAC peaks within the initial 45 min, respectively.

TABLE 10 Dissolution of Compound A and SNAC from tablet composition G pHof dissolution media Disso- 2.5 6.8 lution Compound A SNAC Compound ASNAC time released released released released (min) (% of total) (% oftotal) (% of total) (% of total) 0 0 0  0  0 5 9 17 — — 10 16 24 — — 1521 26 38 49 20 25 28 — — 30 32 28 70 79 45 39 28 85 92 60 43 26 91 96120 — — 95 101 

Example 9 Dissolution of GLP-1 and SNAC from Tablet Composition H

The dissolution of Compound A and SNAC from tablet composition H wasdetermined using Assay (I) described herein. The results are shown inTable 11. The results show that SNAC is released faster than Compound Aduring the initial 20 min of dissolution. Furthermore, it shows that thedifference between the faster release of SNAC compared to Compound A isthe largest in the dissolution medium with the pH-value of 2.5. Lastly,the data shows that in a dissolution medium with a pH-value of 2.5 theamount of dissolved SNAC peaks within the initial 30 min.

TABLE 11 Dissolution of Compound A and SNAC from tablet composition H pHof dissolution media Disso- 2.5 6.8 lution Compound A SNAC Compound ASNAC time released released released released (min) (% of total) (% oftotal) (% of total) (% of total) 0 0 0  0  0 5 10 19 — — 10 19 31 — — 1526 37 37 47 20 31 38 — — 30 36 34 63 75 45 42 29 74 83 60 46 27 79 87120 — — 89 97

Example 10 Bioavailability of GLP-1 in Dogs from Tablet Compositions G-H

Bioavailability of GLP-1 from tablet compositions G-H was determined indogs according to Assay (II) described herein. The results are shown inTable 12.

TABLE 12 Bioavailability of GLP-1 in dogs from tablet compositions G-HBioavailability of GLP-1 in dogs Tablet composition (% F) G 2.1 H 2.5

The results show that tablet composition G provided a bioavailability of2.1%. The results show that tablet composition H provided abioavailability of 2.5%.

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

The invention claimed is:
 1. A solid dosage pharmaceutical compositioncomprising: (a) a first type of granules comprising at least 75% (w/w)of sodium N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC) and lessthan 10% (w/w) of a lubricant; and (b) a second type of granulescomprising semaglutide, at least 15% (w/w) of a filler, and less than40% (w/w) of a binder.
 2. The composition according to claim 1, whereinthe lubricant is magnesium stearate.
 3. The composition according toclaim 1, wherein the lubricant is 1-3% (w/w) of the first granule. 4.The composition according to claim 3, wherein the lubricant is magnesiumstearate.
 5. The composition according to claim 1, wherein the filler ismicrocrystalline cellulose.
 6. The composition according to claim 1,wherein the filler is 50-75% (w/w) of the second granule.
 7. Thecomposition according to claim 6, wherein the filler is microcrystallinecellulose.
 8. The composition according to claim 1, wherein the binderis povidone.
 9. The composition according to claim 1, wherein the binderis 15-25% (w/w) of the second granule.
 10. The composition according toclaim 9, wherein the binder is povidone.
 11. The composition accordingto claim 1, further comprising a filler in the first granule.
 12. Thecomposition according to claim 11, wherein the filler ismicrocrystalline cellulose.
 13. The composition according to claim 11,wherein the filler is less than 20% (w/w) of the first granule.
 14. Thecomposition according to claim 13, wherein the filler ismicrocrystalline cellulose.
 15. The composition according to claim 11,wherein the filler is 10-20% (w/w) of the first granule.
 16. Thecomposition according to claim 15, wherein the filler ismicrocrystalline cellulose.
 17. The composition according to claim 14,wherein the filler is 14-17% (w/w) of the granule.
 18. The compositionaccording to claim 17, wherein the filler is microcrystalline cellulose.19. The composition according to claim 1, wherein the weight of thecomposition is in the range of 150 mg to 1000 mg.
 20. The compositionaccording to claim 1, wherein the lubricant is magnesium stearate, thefiller is microcrystalline cellulose, and the binder is povidone. 21.The composition according to claim 1, wherein the SNAC is 80-86% (w/w)of the first granule, the lubricant is 1-3% (w/w) of the first granule,the filler is 50-75% (w/w) of the second granule, and the binder is15-25% (w/w) of the second granule.
 22. The composition according toclaim 21, wherein the lubricant is magnesium stearate, the filler ismicrocrystalline cellulose, and the binder is povidone.
 23. Thecomposition according to claim 1, further comprising lubricant outsidethe first type of granules and second type of granules.
 24. Thecomposition according to claim 23, wherein the lubricant is magnesiumstearate.
 25. The composition according to claim 22, further comprisingmagnesium stearate outside the first type of granules and second type ofgranules.
 26. The composition according to claim 25, wherein themagnesium stearate outside the first type of granules and the secondtype of granules is in an amount of 2 mg.
 27. The composition accordingto claim 1, wherein the composition comprises at least 60% (w/w) of theSNAC.
 28. The composition according to claim 27, wherein the compositioncomprises at least 70% (w/w) of the SNAC.
 29. The composition accordingto claim 22, wherein the composition comprises at least 60% (w/w) of theSNAC.
 30. The composition according to claim 29, wherein the compositioncomprises at least 70% (w/w) of the SNAC.